Cancer comprises a group of malignant neoplasms that can be divided into two categories, carcinoma, comprising a majority of the cases observed in the clinics, and other less frequent cancers, which include leukaemia, lymphoma, central nervous system tumours and sarcoma. Carcinomas have their origin in epithelial tissues while sarcomas develop from connective tissues and those structures that had their origin in mesoderm tissues. Sarcomas can affect, for instance, muscle or bone and occur in the bones, bladder, kidneys, liver, lung, parotid or spleen.
Cancer is invasive and tends to metastasise to new sites. It spreads directly into surrounding tissues and also may be disseminated through the lymphatic and circulatory systems. Many treatments are available for cancer, including surgery and radiation for localised disease, and drugs. However, the efficacy of available treatments on many cancer types is limited, and new, improved forms of treatment showing clinical benefit are needed. This is especially true for those patients presenting with advanced and/or metastatic disease. It is also true for patients relapsing with progressive disease after having been previously treated with established therapies for which further treatment with the same therapy is mostly ineffective due to acquisition of resistance or to limitations in administration of the therapies due to associated toxicities.
Chemotherapy plays a significant part in cancer treatment, as it is required for treatment of advanced cancers with distant metastasis and often helpful for tumour reduction before surgery, and many anticancer drugs have been developed based on various modes of action.
Dehydrodidemnin B, now known as aplidine, is the subject of WO91/04985. It is related to compounds known as didemnins, and has the following structure:

Further information on aplidine is to be found in, for example:    Jimeno, J., “Exploitation of marine microorganisms and invertebrates: Anticancer drugs from marine origin”, IBC Conf Discov Drugs from Nat Novel Approaches New Sources (Dec 8-9, London) 1994, 1994    Faircloth, G. et al., “Dehydrodidemnin B (DDM) a new marine derived anticancer agent (MDA) with activity against experimental tumour models”, 9th NCI-EORTC Symp New Drugs Cancer Ther (March 12-15, Amsterdam) 1996, Abst 111    Sakai, R. et al., “Structure-activity relationships of the didemnins”, Journal of Medicinal Chemistry 1996, 39 (14): 2819    Urdiales, J. L. et al., “Antiproliferative effect of dehydrodidemnin B (DDB), a depsipeptide isolated from Mediterranean tunicates”, Cancer Letters 1996, 102(1-2): 31    Faircloth, G. et al., “Preclinical characterization of aplidine (APD), a new marine anticancer depsipeptide (MADEP)”, Proc Amer Assoc Cancer Res 1997, 38: Abst 692    Depenbrock, H. et al., “In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells”, British Journal of Cancer 1998, 78(6): 739    Faircloth, G. et al., “Aplidine (aplidine) is a novel marine-derived depsipeptide with in vivo antitumour activity”, Proc Amer Assoc Cancer Res 1998, 39: Abst 1551    Faircloth, G. et al., “Preclinical development of aplidine, a novel marine-derived agent with potent antitumour activity”, 10th NCI-EORTC Symp New Drugs Cancer Ther (June 16-19, Amsterdam) 1998, Abst 129    Mastbergen, S. C. et al., “Cytotoxicity and neurocytoxicity of aplidine, a new marine anticancer agent evaluated using in vitro assays”, 10th NCI-EORTC Symp New Drugs Cancer Ther (June 16-19, Amsterdam) 1998, Abst 131
In preclinical studies, aplidine had dose-dependent cytotoxic activity against the two epithelial-like cell lines, CT-1 and CT-2, and the human colon cancer cell line, HT-29. The most proliferative line, CT-2, was the most sensitive to aplidine. In addition the compound decreased ornithine decarboxylase activity in all three cell lines (Lobo C, Garcia-Pozo S G, et al. Effect of dehydrodidemnin B on human colon carcinoma cell lines. Anticancer Research. 17: 333-336, Jan-Feb 1997). In a similar study, aplidine 50 mmol/L inhibited the growth of the breast cancer cell lines, MDA-MB231 and MCF-7 by 17 and 47%, respectively. A significant increase in spermidine and spermine was observed in the treated cells (Gomezfabre P M, Depedro E, et al. Polyamine contents of human breast cancer cells treated with the cytotoxic agents chlorpheniramine and dehydrodidemnin B. Cancer Letters. 113: 141-144, 26 Feb 1997). Flow cytometric analysis showed that aplidine did not induce any apparent cell cycle pertubations (Erba E, Balconi G, et al. Cell cycle phases pertubations induced by new natural marine compounds. Annals of Oncology. 7 (Suppl. 1): 82, 1996). In mice, aplidine was active against implanted P388 leukaemia and B16 melanoma, with an optimal dose of 160 micro/kg. Unlike didemnin B, aplidine was active in SC implanted lewis lung carcinomas (Faircloth G, Rinehart K, et al. Dehydrodidemnin B a new marine derived anticancer agent with activity against experimental tumour models. Annals of Oncology. 7 (Suppl. 1): 34, 1996).
Continuous exposure to low concentrations of aplidine inhibited the growth of a number of tumour cell lines, including non-Hodgkin's lymphoma, melanoma and breast, melanoma, ovarian and non-small cell lung cancers. The magnitude of effect was dependent on the time of exposure and appeared to be achievable at non-myelotoxic concentrations. Non-small cell lung cancer, breast cancer and melanoma cell lines were sensitive to a continuous exposure to aplidine at concentrations of >=0.001 micromol/L. Aplidine had similar toxicity to doxorubicin against clonogenic haematopoietic stem cells (Depenbrock H, Peter R, et al. In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells. British Journal of Cancer. 78: 739-744, No. 6, September 1998).
Aplidine had significant activity against mice bearing human cancer xenografts. At a maximum tolerated dose of 2.1 mg/kg, aplidine produced near complete remissions in some animals with a treated/control (T/C) tumour ratio of 9%. At 1.25 mg/kg, significant activity was seen against gastric tumours (T/C 14%) and prostate tumour growth inhibition was also observed (T/C 25%) (Faircloth G, Grant W, et al. Preclinical development of aplidine, a novel marine-derived agent with potent antitumour activity. Annals of Oncology. 9 (Suppl. 2): 34, 1998).
Aplidine is related to other compounds of potential use against cancer, notably the didemnins. Aplidine is itself a dehydrodidemnin.
Examples of the related didmenins and other such compounds, which we generally refer to as aplidine analogues, are to be found in:    a) Rinehart K L, Kishore V, Bible K C, Sakai R, Sullins D W, Li K M. Didemnins and tunichlorin: novel natural products from the marine tunicate Trididemnum solidum.            J Nat Prod. 1988 January-February; 51(1):1-21.        Erratum in:        J Nat Prod 1988 May-June; 51(3):624            b) Rinehart K L Jr, Gloer J B, Wilson G R, Hughes R G Jr, Li L H, Renis H E, McGovren J P.            Antiviral and antitumor compounds from tunicates.        Fed Proc. 1983 January; 42(1):87-90.            c) Rinehart K L Jr, Gloer J B, Hughes R G Jr, Renis H E, McGovren J P, Swynenberg E B, Stringfellow D A, Kuentzel S L, Li L H.            Didemnins: antiviral and antitumor depsipeptides from a caribbean tunicate.        Science. May 22, 1981; 212(4497):933-5.            d) Vervoort H, Fenical W, Epifanio R A.            Tamandarins A and B: new cytotoxic depsipeptides from a Brazilian ascidian of the family Didemnidae.        J Org Chem. Feb. 11, 2000; 65(3):782-92.            e) PCT/GB01/02901.            Synthetic methods for aplidine and new antitumoral derivatives Filing Date 2 Jul. 2001        
The article (d) relates to aplidine analogues called tamandarines, notably tamandarine A and tamandarine B:
